Background

Glucocorticoids exert a myriad of metabolic effects mediated predominantly via binding to the glucocorticoid receptor (GR). The GR is known to exert sexually dimorphic effects, possibly via interaction with the androgen receptor (AR), but it is unclear if such crosstalk plays a role in metabolic tissues.

Objective and hypotheses

Our objective is to investigate if glucocorticoid-androgen crosstalk exists in metabolic tissues. We hypothesize that androgens modulate GR signaling in metabolic tissues.

Methods

We collected metabolic tissues from male C57BL/6J mice (N=6-7/group) subjected to: 1) vehicle-treatment, 2) GR agonist corticosterone, 3) corticosterone + AR agonist dihydrotestosterone and 4) corticosterone + AR antagonist enzalutamide. Local glucocorticoid levels were determined by mass spectrometry. Expression of glucocorticoid-responsive genes in white adipose tissue (WAT), liver and brown adipose tissue (BAT) was determined by RT-qPCR and western blot. To evaluate crosstalk in vitro, cultured white and brown adipocytes were incubated with a combination of glucocorticoids and androgens and expression of glucocorticoid-responsive genes was determined by RT-qPCR.

Results

AR agonism enhances GR-regulated transcription in vitro in cultured white and brown adipocytes and in vivo in WAT and BAT. Conversely, AR antagonism attenuates GR-regulated transcription in WAT and liver. In WAT, we found that AR antagonism lowers active glucocorticoid levels via inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)-mediated turnover. In liver, attenuated GR activity was independent of 11β-HSD1 status and glucocorticoid ligand levels.

Conclusion

We show that glucocorticoid-androgen crosstalk exists in metabolic tissues. The mechanisms underlying this are tissue-specific. Further research is warranted to delineate the relative contribution of glucocorticoid-androgen crosstalk to metabolic pathways.